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Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease

Abstract

The entorhinal cortex has been implicated in the early stages of Alzheimer's disease, which is characterized by changes in the tau protein and in the cleaved fragments of the amyloid precursor protein (APP). We used a high-resolution functional magnetic resonance imaging (fMRI) variant that can map metabolic defects in patients and mouse models to address basic questions about entorhinal cortex pathophysiology. The entorhinal cortex is divided into functionally distinct regions, the medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC), and we exploited the high-resolution capabilities of the fMRI variant to ask whether either of them was affected in patients with preclinical Alzheimer's disease. Next, we imaged three mouse models of disease to clarify how tau and APP relate to entorhinal cortex dysfunction and to determine whether the entorhinal cortex can act as a source of dysfunction observed in other cortical areas. We found that the LEC was affected in preclinical disease, that LEC dysfunction could spread to the parietal cortex during preclinical disease and that APP expression potentiated tau toxicity in driving LEC dysfunction, thereby helping to explain regional vulnerability in the disease.

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Figure 1: Whole-brain ROI analysis identified dysfunction in the entorhinal cortex and other cortical regions in preclinical Alzheimer's disease.
Figure 2: Voxel-based analysis pinpoints dysfunction in preclinical Alzheimer's disease to the LEC.
Figure 3: The LEC is affected by tau and APP coexpression and leads to cortical dysfunction.
Figure 4: Patterns of cortical spread in mouse models overlap with patterns observed in preclinical Alzheimer's disease.
Figure 5: APP expression acts to potentiate and accelerate tau toxicity in the LEC.
Figure 6: Mapping histological markers of tau and APP in mouse models.
Figure 7: The LEC shows evidence of high metabolism in young unaffected individuals.

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References

  1. Braak, H. & Del Tredici, K. Alzheimer's disease: pathogenesis and prevention. Alzheimers Dement. 8, 227–233 (2012).

    Article  CAS  PubMed  Google Scholar 

  2. Gómez-Isla, T. et al. Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer's disease. J. Neurosci. 16, 4491–4500 (1996).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Whitwell, J.L. et al. 3D maps from multiple MRI illustrate changing atrophy patterns as subjects progress from mild cognitive impairment to Alzheimer's disease. Brain 130, 1777–1786 (2007).

    Article  PubMed  Google Scholar 

  4. Moreno, H. et al. Imaging the abeta-related neurotoxicity of Alzheimer disease. Arch. Neurol. 64, 1467–1477 (2007).

    Article  PubMed  Google Scholar 

  5. Näslund, J. et al. Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. J. Am. Med. Assoc. 283, 1571–1577 (2000).

    Article  Google Scholar 

  6. Lue, L.F. et al. Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am. J. Pathol. 155, 853–862 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Desikan, R.S. et al. Amyloid-beta–associated clinical decline occurs only in the presence of elevated P-tau. Arch. Neurol. 69, 709–713 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Canto, C.B. & Witter, M.P. Cellular properties of principal neurons in the rat entorhinal cortex. I. The lateral entorhinal cortex. Hippocampus 22, 1256–1276 (2012).

    Article  PubMed  Google Scholar 

  9. Canto, C.B. & Witter, M.P. Cellular properties of principal neurons in the rat entorhinal cortex. II. The medial entorhinal cortex. Hippocampus 22, 1277–1299 (2012).

    Article  PubMed  Google Scholar 

  10. Tsao, A., Moser, M.B. & Moser, E.I. Traces of experience in the lateral entorhinal cortex. Curr. Biol. 23, 399–405 (2013).

    Article  CAS  PubMed  Google Scholar 

  11. Canto, C.B., Wouterlood, F.G. & Witter, M.P. What does the anatomical organization of the entorhinal cortex tell us? Neural Plast. 2008, 381243 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Selkoe, D.J. Alzheimer's disease is a synaptic failure. Science 298, 789–791 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Sperling, R.A. et al. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 7, 280–292 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Lin, W., Celik, A. & Paczynski, R.P. Regional cerebral blood volume: a comparison of the dynamic imaging and the steady state methods. J. Magn. Reson. Imaging 9, 44–52 (1999).

    Article  CAS  PubMed  Google Scholar 

  15. Raichle, M.E. Positron emission tomography. Annu. Rev. Neurosci. 6, 249–267 (1983).

    Article  CAS  PubMed  Google Scholar 

  16. Belliveau, J.W. et al. Functional mapping of the human visual cortex by magnetic resonance imaging. Science 254, 716–719 (1991).

    Article  CAS  PubMed  Google Scholar 

  17. González, R.G. et al. Functional MR in the evaluation of dementia: correlation of abnormal dynamic cerebral blood volume measurements with changes in cerebral metabolism on positron emission tomography with fludeoxyglucose F 18. AJNR Am. J. Neuroradiol. 16, 1763–1770 (1995).

    PubMed  Google Scholar 

  18. Small, S.A., Chawla, M.K., Buonocore, M., Rapp, P.R. & Barnes, C.A. From the cover: imaging correlates of brain function in monkeys and rats isolates a hippocampal subregion differentially vulnerable to aging. Proc. Natl. Acad. Sci. USA 101, 7181–7186 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Liu, L. et al. Trans-synaptic spread of tau pathology in vivo. PLoS ONE 7, e31302 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. de Calignon, A. et al. Propagation of tau pathology in a model of early Alzheimer's disease. Neuron 73, 685–697 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Harris, J.A. et al. Transsynaptic progression of amyloid-beta–induced neuronal dysfunction within the entorhinal-hippocampal network. Neuron 68, 428–441 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sabuncu, M.R., Yeo, B.T., Van Leemput, K., Vercauteren, T. & Golland, P. Asymmetric image-template registration. Med. Image Comput. Comput. Assist. Interv. 12, 565–573 (2009).

    PubMed  PubMed Central  Google Scholar 

  23. Brickman, A.M., Stern, Y. & Small, S.A. Hippocampal subregions differentially associate with standardized memory tests. Hippocampus 21, 923–928 (2011).

    PubMed  Google Scholar 

  24. Elias, M.F. et al. The preclinical phase of alzheimer disease: a 22-year prospective study of the Framingham Cohort. Arch. Neurol. 57, 808–813 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Yasuda, M. & Mayford, M.R. CaMKII activation in the entorhinal cortex disrupts previously encoded spatial memory. Neuron 50, 309–318 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Moreno, H., Hua, F., Brown, T. & Small, S. Longitudinal mapping of mouse cerebral blood volume with MRI. NMR Biomed. 19, 535–543 (2006).

    Article  PubMed  Google Scholar 

  27. Lewis, J. et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293, 1487–1491 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Jicha, G.A., Berenfeld, B. & Davies, P. Sequence requirements for formation of conformational variants of tau similar to those found in Alzheimer's disease. J. Neurosci. Res. 55, 713–723 (1999).

    Article  CAS  PubMed  Google Scholar 

  29. Hevner, R.F. & Wong-Riley, M.T. Entorhinal cortex of the human, monkey, and rat: metabolic map as revealed by cytochrome oxidase. J. Comp. Neurol. 326, 451–469 (1992).

    Article  CAS  PubMed  Google Scholar 

  30. Solodkin, A. & Van Hoesen, G.W. Entorhinal cortex modules of the human brain. J. Comp. Neurol. 365, 610–617 (1996).

    Article  CAS  PubMed  Google Scholar 

  31. Kageyama, G.H. & Wong-Riley, M.T. Histochemical localization of cytochrome oxidase in the hippocampus: correlation with specific neuronal types and afferent pathways. Neuroscience 7, 2337–2361 (1982).

    Article  CAS  PubMed  Google Scholar 

  32. Schon, K., Hasselmo, M.E., Lopresti, M.L., Tricarico, M.D. & Stern, C.E. Persistence of parahippocampal representation in the absence of stimulus input enhances long-term encoding: a functional magnetic resonance imaging study of subsequent memory after a delayed match-to-sample task. J. Neurosci. 24, 11088–11097 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Olsen, R.K. et al. Performance-related sustained and anticipatory activity in human medial temporal lobe during delayed match-to-sample. J. Neurosci. 29, 11880–11890 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Suzuki, W.A. & Amaral, D.G. Perirhinal and parahippocampal cortices of the macaque monkey: cortical afferents. J. Comp. Neurol. 350, 497–533 (1994).

    Article  CAS  PubMed  Google Scholar 

  35. Young, B.J., Otto, T., Fox, G.D. & Eichenbaum, H. Memory representation within the parahippocampal region. J. Neurosci. 17, 5183–5195 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Albert, M.S. The ageing brain: normal and abnormal memory. Phil. Trans. R. Soc. Lond. B 352, 1703–1709 (1997).

    Article  CAS  Google Scholar 

  37. Petersen, R.C., Smith, G., Kokmen, E., Ivnik, R.J. & Tangalos, E.G. Memory function in normal aging. Neurology 42, 396–401 (1992).

    Article  CAS  PubMed  Google Scholar 

  38. Stranahan, A.M., Haberman, R.P. & Gallagher, M. Cognitive decline is associated with reduced reelin expression in the entorhinal cortex of aged rats. Cereb. Cortex 21, 392–400 (2011).

    Article  PubMed  Google Scholar 

  39. Meguro, K. et al. Neocortical and hippocampal glucose hypometabolism following neurotoxic lesions of the entorhinal and perirhinal cortices in the non-human primate as shown by PET. Implications for Alzheimer's disease. Brain 122, 1519–1531 (1999).

    Article  PubMed  Google Scholar 

  40. Klunk, W.E. et al. Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann. Neurol. 55, 306–319 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Kageyama, G.H. & Wong-Riley, M.T. Histochemical localization of cytochrome oxidase in the hippocampus: correlation with specific neuronal types and afferent pathways. Neuroscience 7, 2337–2361 (1982).

    Article  CAS  PubMed  Google Scholar 

  42. Das, U. et al. Activity-induced convergence of APP and BACE-1 in acidic microdomains via an endocytosis-dependent pathway. Neuron 79, 447–460 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ittner, L.M. et al. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. Cell 142, 387–397 (2010).

    Article  CAS  PubMed  Google Scholar 

  44. Sapir, T., Frotscher, M., Levy, T., Mandelkow, E.M. & Reiner, O. Tau's role in the developing brain: implications for intellectual disability. Hum. Mol. Genet. 21, 1681–1692 (2012).

    Article  CAS  PubMed  Google Scholar 

  45. Brickman, A.M. et al. Brain morphology in older African Americans, Caribbean Hispanics, and whites from northern Manhattan. Arch. Neurol. 65, 1053–1061 (2008).

    PubMed  PubMed Central  Google Scholar 

  46. Stern, Y. et al. Diagnosis of dementia in a heterogeneous population. Development of a neuropsychological paradigm-based diagnosis of dementia and quantified correction for the effects of education. Arch. Neurol. 49, 453–460 (1992).

    Article  CAS  PubMed  Google Scholar 

  47. McKhann, G. et al. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 34, 939–944 (1984).

    Article  CAS  PubMed  Google Scholar 

  48. Hughes, C.P., Berg, L., Danziger, W.L., Coben, L.A. & Martin, R.L. A new clinical scale for the staging of dementia. Br. J. Psychiatry 140, 566–572 (1982).

    Article  CAS  PubMed  Google Scholar 

  49. Manly, J.J. et al. Frequency and course of mild cognitive impairment in a multiethnic community. Ann. Neurol. 63, 494–506 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Santacruz, K. et al. Tau suppression in a neurodegenerative mouse model improves memory function. Science 309, 476–481 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Jankowsky, J.L. et al. Environmental enrichment mitigates cognitive deficits in a mouse model of Alzheimer's disease. J. Neurosci. 25, 5217–5224 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Moreno, H., Hua, F., Brown, T. & Small, S. Longitudinal mapping of mouse cerebral blood volume with MRI. NMR Biomed. 19, 535–543 (2006).

    Article  PubMed  Google Scholar 

  53. Reuter, M., Rosas, H.D. & Fischl, B. Highly accurate inverse consistent registration: a robust approach. Neuroimage 53, 1181–1196 (2010).

    PubMed  Google Scholar 

  54. Frangi, A., Niessen, W., Vincken, K. & Viergever, M. Multiscale vessel enhancement filtering. Med. Image Comput. Comput, Assist. Interv. 1496, 130–137 (1998).

    Google Scholar 

  55. Desikan, R.S. et al. An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage 31, 968–980 (2006).

    Article  PubMed  Google Scholar 

  56. Tustison, N.J. et al. N4ITK: improved N3 bias correction. IEEE Trans. Med. Imaging 29, 1310–1320 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Richards, K. et al. Segmentation of the mouse hippocampal formation in magnetic resonance images. Neuroimage 58, 732–740 (2011).

    Article  PubMed  Google Scholar 

  58. Zeineh, M.M., Engel, S.A. & Bookheimer, S.Y. Application of cortical unfolding techniques to functional MRI of the human hippocampal region. Neuroimage 11, 668–683 (2000).

    Article  CAS  PubMed  Google Scholar 

  59. Mueller, S.G. et al. Measurement of hippocampal subfields and age-related changes with high resolution MRI at 4T. Neurobiol. Aging 28, 719–726 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Paxinos, G. & Franklin, K. The Mouse Brain in Stereotaxic Coordinates (Academic Press, 2001).

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Acknowledgements

This work was supported by US National Institutes of Health grants AG034618 and AG025161 to S.A.S., AG07232 and AG037212 to R.M., NS074874 to K.E.D., and HL094423 to R.S.

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U.A.K. performed the mouse and human fMRI analysis and wrote the manuscript. L.L. helped with mouse breeding and performed the histological analyses in mice models. F.A.P. performed the human fMRI post-processing. D.E.B. performed the microarray and other molecular analyses. C.P.P. helped with the histological analyses and mouse breeding. R.S. recruited the young human subjects. R.M. recruited and characterized the older human subjects. K.E.D. supervised the generation and histological analyses in the mouse models and wrote the manuscript. S.A.S. designed the studies, helped with the statistical analyses and wrote the manuscript.

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Correspondence to Karen E Duff or Scott A Small.

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Khan, U., Liu, L., Provenzano, F. et al. Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease. Nat Neurosci 17, 304–311 (2014). https://doi.org/10.1038/nn.3606

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